It is important that pharmaceutical products be effective and safe. Even if a pharmaceutical product is effective and safe immediately after production, if the drug is easily decomposed or denatured during distribution of the pharmaceutical product, it is not considered to be effective and safe as a pharmaceutical product. Therefore, the stability of the drug is extremely important for pharmaceutical products.
To secure effectiveness and safety of a pharmaceutical product, not only the effectiveness and safety of the active ingredient itself are important but also the properties of the pharmaceutical preparation, such as the drug dissolution property in the body and the like, are extremely important. For example, when dissolution of the drug from the pharmaceutical preparation is too late, the blood concentration of the drug does not reach an effective level, and the expected efficacy may not be sufficiently exhibited. On the other hand, when dissolution of the drug from the pharmaceutical preparation is too fast, the blood concentration of the drug increases sharply, causing a high risk of side effects.
In other words, pharmaceutical products are required to ensure the stability of the drug and a certain level of the drug dissolution, in addition to the effectiveness and safety.
Meanwhile, the drug dissolution property is known to correlate with the solubility thereof. In general, lower solubility of a drug is known to cause slower drug dissolution property.
Incidentally, benzimidazole derivative (I) having a strong angiotensin II receptor antagonistic activity
wherein R1 is a monocyclic nitrogen-comprising heterocyclic group having a hydrogen atom that can be deprotonized, R2 is an esterified carboxyl group, and R3 is an optionally substituted lower alkyl, or a salt thereof (hereinafter to be sometimes referred to as compound (I)), particularly, a salt of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (patent document 1) is a promising therapeutic drug for hypertension and the like. However, the properties of a pharmaceutical preparation need to be adjusted to stabilize compound (I) because compound (I) is unstable in the neutral pH range, at which pharmaceutical preparations are generally produced. Nevertheless, the solubility of compound (I) is low at the pH range where compound (I) is stable. In addition, a combination drug product composed of compound (I) and active ingredients such as calcium antagonist and the like cannot be easily formulated into, a pharmaceutical preparation superior in the stability and dissolution property due to the difference in chemical properties.
As combination drug product, a combination of a compound having an angiotensin II antagonistic activity and a compound having a calcium antagonistic action (patent document 2) and an oral solid preparation containing acetaminophen obtained by a separating granulation method to suppress the unpleasant taste of acetaminophen and prevent discoloration thereof (patent document 3) are known. However, a combination drug product of compound (I) and a calcium antagonist, which simultaneously achieves stability and solubility, i.e., dissolution property, of the drug has not been known.